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1 Controlled Release Reservoir-Membrane Systems. 2 Overview History Membrane devices with constant release rate Diffusion cell experiments with first.

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Presentation on theme: "1 Controlled Release Reservoir-Membrane Systems. 2 Overview History Membrane devices with constant release rate Diffusion cell experiments with first."— Presentation transcript:

1 1 Controlled Release Reservoir-Membrane Systems

2 2 Overview History Membrane devices with constant release rate Diffusion cell experiments with first order release Burst and lag effects in membrane systems Diffusion coefficients Membrane materials Applications of membrane systems

3 3 Components of membrane systems Mechanism: diffusion-controlled Driving force: ΔC across membrane Medium: polymer membrane or liquid-filled pores Resistance: function of film thickness, diffusivity of solute in medium Membrane usually interfaces with biological site. Biocompatibility may be important.

4 4 History of Membrane Systems Folkman and Long (1966 patent) Folkman studied effect of thyroid hormone on heart block Folkman needed non-inflammatory vehicle for extended release of hormone Long performed a photographic study of turbulence induced by artificial Si rubber heart valves Long noticed that certain dyes permeated Si rubber

5 5 History (continued) Folkman and Long tested diffusion of dyes and drugs across Si tube walls.  Observed that oil-soluble, low MW (<1000) dyes permeated membrane  Observed that water-soluble, high MW dyes did not. This was the beginning of a research EXPLOSION! First CR device (late 1960s) was use of hormones for contraception, which has now been widely studied.

6 6 Theory Fick’s First Law Relate C m1 and C m2 to surrounding concentrations Rewrite Flux Body acts as a sink (C 2 ≈0) Constant rate can be achieved if C 1 is kept constant. membrane C1C1 C2C2 h C m1 C m2 C 1

7 7 What if C 1 is not constant? Common situation in diffusion cell  Drug is depleted from reservoir (1)  Drug accumulates in receiver (2) membrane C1C1 C2C2 h C m1 C m2

8 8 Diffusion cell: Derivation of M 1 (t) Fick’s Law USS Mass Balance Combine USSMB with Fick’s Law Rearrange

9 9 Diffusion cell Integrate with IC: C 1 -C 2 = C 1 0 -C 2 0  Apply mass balance  Substitute

10 10 Diffusion cell Rearrange (see details) Differentiate to find release rate First Order Release Rate

11 11 Release profile for diffusion cell

12 12 Data Analysis Diffusion Cell Experiment provides data for C 1 vs t Rearrange equation for M 1 Taking natural log of both sides results in linearized eqn

13 13 Graphing diffusion cell data Experiment:  L=2.5x10 -3 cm  V 1 =V 2 =3 cm 3  A = 2 cm 2  K = 1 (water-filled pores) Analysis m = s -1 m = Solve for D D=1.0 x cm 2 /s

14 14 Burst and Lag Effects Previous analysis was based on steady-state flux in membrane membrane C1C1 C2C2 h C m1 C m2

15 15 Burst and Lag Lag membrane C1C1 C2C2 h C m1 C m2 Membrane exposed to reservoir at t=0 Initially no drug in membrane Takes time to build up SS concentration gradient Burst membrane C1C1 C2C2 h C m1 C m2 Device stored before use Initial concentration of drug in membrane = C 1 Takes time for drug to desorb and achieve SS concentration gradient

16 16 Lag Time & Burst Effect Equations for the amount of drug released after SS is attained in the membrane: Lag Burst Equations result from solving transport eqns. (Fick’s 2nd Law) for USS diffusion with relevant ICs; then taking limit as t →∞ Equations These equations are for C1=const; C2=0

17 17 Burst and Lag Effects The lag time is the time required for the solute to appear on the receiver side. It is also the time required to attain a SS concentration profile in the membrane

18 18 Effect of lag and burst Membrane thickness 100 microns D = 1 x cm 2 /s Calculate Lag time and Burst time Repeat for D = 1 x cm 2 /s D = 1 x cm 2 /s D = 1 x cm 2 /s t lag = 2.7 mint lag = 277 min t burst = 5.5 mint burst = 555 min

19 19 Diffusivity values for polymers Function of MW  Greater dependence for solute in polymers than for solute in liquids.  For drugs with <400 MW In water: cm 2 /s

20 20 Diffusion through microporous membranes Molecules move through liquid-filled pores Small molecules do not experience hindered diffusion Porosity 0 < ε <1 Tortuosity typically 1 < τ <5  pathlength is longer than membrane thickness

21 21 Membrane materials Silicone (Silastic – Dow Corning) EVA – Ethylene Vinyl Acetate  EVAc- Ethylene Vinyl Acetate copolymer Entrapped fluids  Hydrogels and microporous membranes

22 22 Silicone membranes Biocompatible and sterilizible High permeability to many steroids Low permeability to ionized species Fick’s law is valid for many compounds D is on the order of  High compared to many polymers

23 23 Applications of Silicone membranes 5 year contraceptive Transderm Nitro patch: mg/cm 2 /day

24 24 EVA Membrane Systems Advantages over silicone  Lower permeability to non-polar compounds offers better rate control  Easier processing and formation of thermoplastic Extrusion, injection molding, film casting  Co-polymers can effect big changes in properties Flexibility, permeability, strength

25 25 Examples of EVA Systems Progestasert  Progesterone contraceptive by ALZA  Intrauterine device, 65 mcg per day for 400 days  Silicone T-shaped tube with 35 mg drug in Si oil

26 26 Examples of EVA Systems Ocusert  Pilocarpine glaucoma treatment system by ALZA  Thin, flexible “contacts” behind eyelid  Use once a week; replaces drops 4 times per day  Releases 20 or 40 mcg per hour  Contains 5-11 mg pilocarpine  Sterilized by irradiation 1.Clear EVA membrane 2.Opaque white sealing ring 3.Pilocarpine reservoir 4.Clear EVA membrane  Oval shape, 6 mm x 13 mm x 0.5 mm  Thin EVA membranes 100 microns thick

27 27 Hydrogel systems Hydrophilic monomers that make cross-linked networks which hold water  Great ease of synthesis  Wide range of properties  D depends on cross-linking agent and water content

28 28 Applications of hydrogels membrane systems Fluoride salts in the mough  0.2 – 1.0 mg/day for 6 months Narcotic agonist – cyclazocine  Prevents opiate effect and is used in rehabilitation Anticancer pouches for direct placement on tumors

29 29 Applications of microporous membranes Microporous Membranes – used in many biomedical applications  Blood oxygenation, dialysis, wound dressings, drug delivery Drug Delivery Applications  Transderm Scop® (scopolamine) —Introduced in 1981 for motion-sickness. Microporous polypropylene membrane. (Alza-Ciba Geigy)  Transderm-Nitro® (nitroglycerin) — For angina patients. Alternative to the brief effects of sublingual nitroglycerin and the messiness of nitroglycerin ointment. Microporous EVA membrane. (Alza-Ciba Geigy)  Catapres-TTS® (clonidine) — Once-a week patch for hypertension replaces up to four daily oral doses. Uses microporous polypropylene membrane. (Alza-Boehringer/Ingelheim)  Estraderm® (estradiol) —Twice-weekly, convenient estrogen replacement therapy. Avoids first pass and therefore uses only a fraction of the drug used in the oral therapy. Uses microporous polypropylene membrane. (Alze-Ciba Geigy)  Duragesic® (fentanyl) —Introduced in 1991 for management of chronic pain via opioid analgesia. Uses microporous polyethylene membrane. (Alza)  NicoDerm® CQ® (nicotine)—smoking-cessation aid in multiple dosage strengths offering maximum control of the drug delivery rate. Uses microporous polypropylene membrane. (Alza-GSK)  Testoderm® and Testoderm® —Introduced in 1994 and 1998, respectively, for hormone replacement therapy in men with a deficiency or absence of testosterone. Microporous EVAc membrane. (Alza-Lederle)

30 30 ALZA’s Transderm Scop Removable strip Rate controlling microporous membrane with highly permeable liquid in pores Foil backing, protective and impermeable Adhesive gel layer with priming dose Reservoir with solid drug in highly permeable matrix Controlled release form maintains low conc of drug, reduces side effects 2.5 cm 2 area 200 mcg priming dose 10 mcg/h for 72 h steady state delivery

31 31 Diffusion Cell Equations Derivation of M 1 (t) Derivation of M 1 (t)

32 32 Burst and Lag effects Ref. Kydonieus, A. Treatise on Controlled Drug Delivery

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